Pyridine, a Six-Membered Heterocycle

Five-Membered Unsaturated Heterocycles 1151 Structures of Pyrrole, Furan, and Thiophene 1152 Electrophilic Substitution Reactions of Pyrrole, Furan, and Thiophene 1153 Pyridine, a Six-Membered Heterocycle Electrophilic Substitution of Pyridine Nucleophilic Substitution of Pyridine Fused-Ring Heterocycles 1158 Nucleic Acids and Nucleotides 1160 Structure of Nucleic Acids 1163 Base Pairing in DNA The Watson-Crick Model Nucleic Acids and Heredity 1166 Replication of DNA 1167... 

Ring expansion of five- to six-membered rings such as oxazole —> pyridine derivatives via a Diels-Alder reaction is a well-established procedure. However, the conversion of a six-membered heterocycle into a five-membered ring system has not been exploited to any great extent, and those systems that have been studied usually involve a cationic species. 

Other kinds of substances besides benzene-like compounds can also be aromatic. For example, the cyclopentadienyl anion and the cycloheptatrienyl cation are aromatic ions. Pyridine, a six-membered, nitrogen-containing heterocycle, is aromatic and resembles benzene electronically. Pyrrole, a hve-membered heterocycle, resembles the cyclopentadienyl anion. 

Compounds in this section comprise indolizines and their hetero-substituted analogues which are fused through the /-edge to a six-membered heterocycle. Where the fused six-membered ring is pyridine, however, these compounds are named not as fused indolizines but as pyrrolonaphthyridines. 

Structure and Nomenclature. The pyridine group consists of a six-membered, heterocyclic, aromatic compound with one nitrogen atom in the ring. The parent compound of this group is pyridine I with ring positions numbered as shown. Alternative denotations of the I. 2, and 4 positions in the ring are alpha, heta, and gamma, respectively. 

Pyrimidine is a six-membered heterocycle with two nitrogen atoms situated in a 1,3- arrangement. Both nitrogen atoms are like the pyridine nitrogen. Each has its lone pair of electrons in the sp2 hybrid orbital in the plane of the aromatic ring. These lone pairs are not needed for the aromatic sextet, and they are basic, like the lone pair of pyridine. 

Pyrimidine is a six-membered heterocycle with two nitrogen atoms situated in a 1,3 arrangement. Both nitrogen atoms are like the pyridine nitrogen. Each has its lone pair... 

Insertion of a ttvo-carbon unit into a five-membered metallacycle may afford formation of a six-membered carbocycle (Eq. 60), such as a benzene derivative via a formal [2+2+2] aromatization of three alkynes. Similarly, insertion of a C-X unit such as a nitrile into a five-membered metallacycle may afford formation of a six-membered heterocycle, such as a pyridine derivative (Eq. 60). In recent years, Takahashi laboratory and other laboratories have developed a number of synthetically useful methods for six-membered cyclic compounds by taking advantage of five-membered metallacycles of zirconocenes and ti-tanocenes [1-5]. 

Several other review articles cover various aspects of tautomerism in six-membered heterocycles. Various aspects of prototropic tautomerism have been covered in a review article by Katritzky [91H(32)329] types of tautomerism, methods of study of aromatic tautomerism, and tautomeric equilibria in pyridines and other six-membered rings. Some generalizations have also been made. Another review article by Kurasawa, which appeared in two parts in 1995, covers, for the most part, the work of that author [95H(41)1805 95H(41)2057]. 

Six-membered heterocycles have also been extensively used to mimic the central pyrazole scaffold of limonabant (382). Merck and Co. has utilised pyiidines (510) [314], and pyrimidines (511) [315] in this capacity. Sanofi-Aventis has also claimed a series of pyridine-based analogues [316], as exemplified by (512) and additionally the non-heteroatom containing terphenyl (513) [317]. 

As six-membered heterocycles are present in a number of natural products and biologically important molecules, solid-phase synthesis of these has been reported very often (Fig. 3.9). Solid-phase synthesis for nearly every six-membered ring including one nitrogen atom are known piperidines (272) [376], tetrahydropyridines (273) [377, 378], dihydropyridines (274) [219, 379, 380], pyridines (275) [349, 381-386], (Scheme 3.37), piperidinones (276) [387], dihydropyridones (277-279) [313, 378, 388-390], pyridinones (280-281) [328, 329] and piperidindiones (282) [391] derivatives. In contrast, the synthesis of six-membered rings with one single oxygen is rarely described. Nevertheless, solid-phase synthesis of dihydropyrans (283-284) [392-394] and tetrahydropyrans (285) [335, 336] has been reported. 

---